Background: Oral carcinoma (OC) remains as one of the most difficult malignancies to cure. Hesa-A is anIranian herbal-marine compound that has shown promising anti-tumor properties on various human cancercells, although the mechanisms of action remain to be addressed. This study was conducted to evaluate the effectof two doses of Hesa-A on mRNA expression of p53 as a main prognosticator of OC. Materials and Methods:60 rats were randomly divided into 5 groups of 12 animals each. Rats in carcinoma groups received 0, 250 and500 mg/kg body weight of Hesa-A three times a day. The two other groups considered as treated and untreatedhealthy groups. At the end of experiment, animals were sacrificed and tongue tissues subjected to H and Estaining and real time PCR. Results: Our results indicated that compared to healthy group, p53 over expressed ~40% in untreated carcinoma group. After treatment with 250mg/kg and 500mg/kg body weights of Hesa-A , p53level dropped by 53.4% and 13.6 %, respectively, compared to untreated carcinoma group (p<0.05, p<0.0001).Moreover, there was a significant relation between p53 mRNA content and observed pathological changes instudied groups (p<0.05). Conclusions: These data provide insights into the mechanism(s) by which Hesa-Aimproves clinical outcome of oral carcinoma by modulation of p53 expression.